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Completed

NCT Number: NCT02164981

A Proof of Concept Study of Intravenous Sodium Nitroprusside in Adults With Symptomatic Schizophrenia

The primary objective of this study is to investigate whether a single infusion of intravenous sodium nitroprusside (0.5 μg/kg/min for 4 hours) is superior to placebo (5% dextrose solution) at in treating positive and negative symptoms of schizophrenia

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Key information

Conditions

Schizophrenia Mental Disorders Schizophrenia Spectrum and Other Psychotic Disorders

Age range

18 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Schizophrenia Clinical Research Program, Massachusetts General Hospital, Boston, Massachusetts, United States

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About this study

This is a phase II proof of concept (POC), multi-center, prospective, randomized, placebo-controlled, Sequential Parallel Comparison Design (SPCD) study, in which a total of 60 subjects with schizophrenia will be enrolled.

The study will be conducted in two stages. The study treatment will be administered in a double-blind fashion for all subjects throughout both stages of the study. A total of 60 subjects with schizophrenia will be randomized in a 1:1:1 ratio to drug-drug sequence [n=20; i.v. sodium nitroprusside (0.5 μg/kg/min for 4 hours) at week 0 and week 2], placebo-drug sequence [n=20; i.v. placebo at week 0 and i.v. sodium nitroprusside (0.5 μg/kg/min for 4 hours) at week 2], and placebo-placebo sequence [n=20; i.v. placebo at week 0 and again at week 2]. The 4-week double-blind phase of treatment will be divided into two phases: Phase 1, from week 0 to week 2, and Phase 2 from week 2 to week 4. At the end of Phase 1 (week 2), the randomized subjects will be assessed and categorized into responders and non-responders, based on 20% or more reduction from baseline in their PANSS total score as per the evaluations at Randomization Visit (week 0). The data from the patients deemed placebo non-responders in phase 1 who go on to either stay on placebo or to receive treatment with sodium nitroprusside will be pooled with the data from Phase 1 from all subjects, according to SPCD.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

Each subject must meet all of the following criteria to be eligible for this study:

  • Males or Females aged 18-65 years inclusive.
  • Primary diagnosis of Schizophrenia established by a structured psychiatric evaluation (SCID) based on Diagnostic and Statistical Manual of Mental Disorders Forth Edition (DSM-IV-TR) criteria.
  • Written informed consent in compliance with 21 CFR part 50 and in accordance with the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines.
  • A Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1994) total score ≥ 70 with a score of > 4 on two or more of the following PANSS items: delusions, conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content.
  • A score of ≥4 on the Clinical Global Impression-Severity (CGI-S) (Guy, 1976).
  • Confirmation of both diagnosis and severity of psychosis symptoms by an independent MGH SAFER interview.
  • Must have ongoing antipsychotic treatment for at least 8 weeks, with a stable dose for at least 4 weeks. Subjects who have failed to achieve clinically-recognized symptom reduction to at least 1 marketed antipsychotic agent, given at a Physician Desk Reference (PDR)-defined therapeutic dose for ≥ 8 weeks during the past 12 months, as assessed by the MGH FAST, will be eligible
  • Understands and is able, willing, and (in the opinion of the investigator) likely to fully comply with the study procedures and restrictions.

Exclusion criteria

Subjects who meet any of the following criteria will be excluded from the study:

  • Subjects with a history of renal insufficiency, congestive heart failure, cardiac arrhythmias or history of myocardial infarction.
  • Subjects with a history of symptomatic orthostatic hypotension defined as sitting to standing systolic blood pressure < 90mmHg or diastolic blood pressure < 60mm Hg with any of the following symptoms: lightheaded or dizzy upon standing, blurry vision, weakness, fainting (syncope), confusion, or nausea.
  • Subjects with any clinically significant abnormalities as determined by medical history, physical exam, clinical and lab evaluation suggestive of an underlying disease state that may, in the opinion of the investigator, confound the results of study, increase risk to the subject, or lead to difficulty complying with the protocol.
  • Subjects on chlorpromazine, PDE-5 inhibitors, nitrites and any medication with CNS effects with the exception of antipsychotic drugs (other than chlorpromazine) anticholinergics, b-adrenergic antagonists, amantadine, biperiden, diphenhydramine, lorazepam, zolpidem, and temazepam.
  • Medications which in the opinion of the PI, and in conjunction with the medical monitor, may be expected to significantly interfere with the metabolism or excretion of sodium nitroprusside, and/or may be associated with a significant drug interaction with sodium nitroprusside that may pose a significant risk to subjects' health and/or confound the study data.
  • Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed at screening visit prior to randomization and prior to baseline at visits 3 and 6. Women enrolled in this trial must use adequate birth control.
  • Subjects with a current (within the last 3 months) DSM-IV-TR diagnosis of alcohol or substance use disorder or dependence (excluding nicotine) as established by the clinical assessment (SCID) at the screening visit will be excluded.
  • Has tested positive for any of the following: cannabis, opioids, cocaine, amphetamines, barbiturates methadone, methamphetamine and phencyclidine at the screening or baseline visits. If positive, the urine drug toxicology screen may be repeated once based on investigator judgment, but due to safety concerns, the result must be negative for the subject to continue in the study.
  • Subjects at imminent risk of suicide or injury to self or others, as per the opinion of the investigator, or history of significant suicide attempt within the last 6 months as per C-SSRS.
  • Subjects that have taken an investigational drug or taken part in a clinical trial within 30 days prior to screening.
  • Any other reason that, in the opinion of the investigator, would compromise patient safety or integrity of the study

Treatment and study plan

Sodium Nitroprusside

Drug

intravenous

Other names: Nitropress

Placebo

Other

Placebo

Other names: 5% dextrose

Primary outcomes

  1. Change in Positive and Negative Syndrome Scale (PANSS) - Total Score - Study Phases 1 and 2

    Time frame: For Phase 1, timeframe is Day 0 and Day 14; Phase 2 timeframe is Day 14 and Day 28

    The Positive and Negative Syndrome Scale (PANSS) will be used to measure symptom severity in this trial. PANSS is a 30-item questionnaire used to evaluate schizophrenia symptoms, based on the clinical interview as well as reports of family members or primary care hospital workers. PANSS consists of Positive scale (7 items), Negative scale (7 items), and General Psychopathological scale (16 items) sections. Each item (symptom) will be scored on a 7-point scale with higher scores representing increasing levels of psychopathology: 1) Absent, 2) Minimal, 3) Mild, 4) Moderate, 5) Moderate severe, 6) Severe, and 7) Extreme. Total score minimum = 30, maximum = 210

Secondary outcomes

  1. PANSS - Positive Subscale - Phases 1 and 2

    Time frame: Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

    The Positive and Negative Syndrome Scale (PANSS) will be used to measure symptom severity in this trial. PANSS is a 30-item questionnaire used to evaluate schizophrenia symptoms, based on the clinical interview as well as reports of family members or primary care hospital workers. PANSS consists of Positive scale (7 items), Negative scale (7 items), and General Psychopathological scale (16 items) sections. Each item (symptom) will be scored on a 7-point scale with higher scores representing increasing levels of psychopathology: 1) Absent, 2) Minimal, 3) Mild, 4) Moderate, 5) Moderate severe, 6) Severe, and 7) Extreme. Positive scale: 7 Items, (minimum score = 7, maximum score = 49)

  2. PANSS - Negative Subscale - Phases 1 and 2

    Time frame: Phase 1 timeframe is Day 0 and Day 14; Phase 2 timeframe is Day 14 and Day 28

    The Positive and Negative Syndrome Scale (PANSS) will be used to measure symptom severity in this trial. PANSS is a 30-item questionnaire used to evaluate schizophrenia symptoms, based on the clinical interview as well as reports of family members or primary care hospital workers. PANSS consists of Positive scale (7 items), Negative scale (7 items), and General Psychopathological scale (16 items) sections. Each item (symptom) will be scored on a 7-point scale with higher scores representing increasing levels of psychopathology: 1) Absent, 2) Minimal, 3) Mild, 4) Moderate, 5) Moderate severe, 6) Severe, and 7) Extreme. Negative scale: 7 Items, (minimum score = 7, maximum score = 49)

  3. PANSS - General Psychopathology Subscale - Phases 1 and 2

    Time frame: Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

    The Positive and Negative Syndrome Scale (PANSS) will be used to measure symptom severity in this trial. PANSS is a 30-item questionnaire used to evaluate schizophrenia symptoms, based on the clinical interview as well as reports of family members or primary care hospital workers. PANSS consists of Positive scale (7 items), Negative scale (7 items), and General Psychopathological scale (16 items) sections. Each item (symptom) will be scored on a 7-point scale with higher scores representing increasing levels of psychopathology: 1) Absent, 2) Minimal, 3) Mild, 4) Moderate, 5) Moderate severe, 6) Severe, and 7) Extreme. General Psychopathology Subscale: 16 Items, (minimum score = 16, maximum score = 112)

  4. Average Percent Change From Baseline in the PANSS Total Score After 2 Weeks of Treatment Using SPCD

    Time frame: For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

    The Positive and Negative Syndrome Scale (PANSS) will be used to measure symptom severity in this trial. PANSS is a 30-item questionnaire used to evaluate schizophrenia symptoms, based on the clinical interview as well as reports of family members or primary care hospital workers. PANSS consists of Positive scale (7 items), Negative scale (7 items), and General Psychopathological scale (16 items) sections. Each item (symptom) will be scored on a 7-point scale with higher scores representing increasing levels of psychopathology: 1) Absent, 2) Minimal, 3) Mild, 4) Moderate, 5) Moderate severe, 6) Severe, and 7) Extreme. Total score minimum = 30, maximum = 210.

  5. Percentage of Subjects With 20% or More Reduction From Baseline in PANSS Total Score After 2 Weeks of Treatment Using SPCD

    Time frame: For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

    The Positive and Negative Syndrome Scale (PANSS) will be used to measure symptom severity in this trial. PANSS is a 30-item questionnaire used to evaluate schizophrenia symptoms, based on the clinical interview as well as reports of family members or primary care hospital workers. PANSS consists of Positive scale (7 items), Negative scale (7 items), and General Psychopathological scale (16 items) sections. Each item (symptom) will be scored on a 7-point scale with higher scores representing increasing levels of psychopathology: 1) Absent, 2) Minimal, 3) Mild, 4) Moderate, 5) Moderate severe, 6) Severe, and 7) Extreme. Total score minimum = 30, maximum = 210.

  6. Average Percent Change From Baseline in the PANSS Positive Subscale Score After 2 Weeks of Treatment Using SPCD

    Time frame: For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

    The Positive and Negative Syndrome Scale (PANSS) will be used to measure symptom severity in this trial. PANSS is a 30-item questionnaire used to evaluate schizophrenia symptoms, based on the clinical interview as well as reports of family members or primary care hospital workers. PANSS consists of Positive scale (7 items), Negative scale (7 items), and General Psychopathological scale (16 items) sections. Each item (symptom) will be scored on a 7-point scale with higher scores representing increasing levels of psychopathology: 1) Absent, 2) Minimal, 3) Mild, 4) Moderate, 5) Moderate severe, 6) Severe, and 7) Extreme. Positive subscore scale: 7 items (minimum score = 7; maximum score = 49)

  7. Average Percent Change From Baseline in the PANSS Negative Subscale Score After 2 Weeks of Treatment Using SPCD

    Time frame: For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

    The Positive and Negative Syndrome Scale (PANSS) will be used to measure symptom severity in this trial. PANSS is a 30-item questionnaire used to evaluate schizophrenia symptoms, based on the clinical interview as well as reports of family members or primary care hospital workers. PANSS consists of Positive scale (7 items), Negative scale (7 items), and General Psychopathological scale (16 items) sections. Each item (symptom) will be scored on a 7-point scale with higher scores representing increasing levels of psychopathology: 1) Absent, 2) Minimal, 3) Mild, 4) Moderate, 5) Moderate severe, 6) Severe, and 7) Extreme. Negative subscore scale: 7 items (minimum score = 7; maximum score = 49)

  8. Average Percent Change From Baseline in the PANSS General Psychopathology Subscale Score After 2 Weeks of Treatment Using SPCD

    Time frame: For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

    The Positive and Negative Syndrome Scale (PANSS) will be used to measure symptom severity in this trial. PANSS is a 30-item questionnaire used to evaluate schizophrenia symptoms, based on the clinical interview as well as reports of family members or primary care hospital workers. PANSS consists of Positive scale (7 items), Negative scale (7 items), and General Psychopathological scale (16 items) sections. Each item (symptom) will be scored on a 7-point scale with higher scores representing increasing levels of psychopathology: 1) Absent, 2) Minimal, 3) Mild, 4) Moderate, 5) Moderate severe, 6) Severe, and 7) Extreme. General Psychopathology subscore scale: 16 items (minimum score = 16; maximum score = 112)

Other outcomes

  1. Change in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) - Phases 1 and 2

    Time frame: Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

    MATRICS: The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB). The MATRICS Consensus Cognitive Battery is the standard tool for assessing cognitive change in trials of cognitive-enhancing agents in schizophrenia. The MCCB domains include: Speed of Processing; Attention/Vigilance; Working Memory; Verbal Learning; Visual Learning; Reasoning & Problem-Solving; and Social Cognition and the battery takes about 80 minutes to complete. The MCCB composite score represents a global measure of cognition. MCCB composite T scores are between 40 and 60 (normal range) and < 40 (below normal range).

  2. Average AIMS Total Scores (Items 1-7) by Group and Timepoint

    Time frame: Baseline 1 (Day -1), 7 Hours Post-Infusion 1, Baseline 2 (Day 13), 7 Hours Post-Infusion 2, Final Follow-Up, including early termination visits

    Abnormal Involuntary Movement Scale (AIMS):

    The AIMS Total Dyskinesia Score was calculated by averaging the first 7 items of the AIMS. The 7 items included in the AIMS Dyskinesia Score are rated on a scale from 0 (no dyskinesia) to 4 (severe dyskinesia). Items 1 through 7 include facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). The AIMS dyskinesia total score ranges from 0 to 4; a higher score reflects increased severity.

  3. Percent of Participants Rated as ≥ "Mild" or as "Yes" on AIMS Items 8-12

    Time frame: Baseline (Day -1), Follow-Up = reported at any assessment thereafter, including 7 hours after Infusions #1 and #2, Baseline 2 (Day 13) and final follow-up, including early termination visits.

    Abnormal Involuntary Movement Scale (AIMS):

    The AIMS is a 12-item anchored score that is clinician administered and scored. Items are scored on a 0 (none) to 4 (severe) basis; items 8-10 deal with global severity; items 11-12 are yes-no questions concerning problems with teeth and/or dentures.

  4. Change in The University of California San Diego (UCSD) Performance-based Skills Assessment Brief (UPSA-B) - Phases 1 and 2

    Time frame: Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

    The University of California San Diego (UCSD) Performance-based Skills Assessment Brief (UPSA-B) consists of two of the five original UPSA domains, finances and communication. Each subscale contributes 50 points; total scores range from 0 to 100 points with higher scores reflecting better performance.

  5. Number of Participants Reporting Suicidal Ideation/Behavior on the Columbia Suicide Severity Rating Scale (C-SSRS)

    Time frame: Screening Visit, Days 3 (Baseline 1), Days 7, 13 (Baseline 2), 21 and 28

    The Columbia Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was developed in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events through any treatment. It is a clinical interview providing a summary of both ideation and behavior that can be administered during any evaluation or risk assessment to identify the level and type of suicidality present. The C-SSRS can also be used during treatment to monitor for clinical worsening or improvement. It contains 5 rating scale questions (yes/no) for suicidal ideation increasing severity and 5 rating scale questions (yes/no) for suicidal behavior of increasing severity. The time frame is for both lifetime and the past six months for the Baseline/Screening scale and since the last visit for the Since Last Visit scale.

  6. Systolic Blood Pressure Per Infusion Phase by Group

    Time frame: Day 0 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours

    Infusion 1 (Day 0) - Systolic Blood Pressure at all time points by group

    "Phase" in this analysis refers to the infusion stage as defined in the protocol.

  7. Diastolic Blood Pressure Per Infusion Phase by Group

    Time frame: Day 0 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours

    Infusion 1 (Day 0) - Diastolic Blood Pressure at all time points by group

    "Phase" in this analysis refers to the infusion stage as defined in the protocol.

  8. Systolic Blood Pressure Per Infusion Phase by Group

    Time frame: Day 14 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours

    Infusion 2 (Day 14) - Systolic Blood Pressure at all time points by group

    "Phase" in this analysis refers to the infusion stage as defined in the protocol.

  9. Phase 2 - Diastolic Blood Pressure Per Infusion Phase by Group

    Time frame: Day 14 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours

    Infusion 2 (Day 14) - Diastolic Blood Pressure at all time points by group

  10. Heart Rate Per Infusion Phase by Group

    Time frame: Day 0 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours

    Infusion 1 (Day 0) - Heart rate at all time points by group

    "Phase" in this analysis refers to the infusion stage as defined in the protocol.

  11. Heart Rate Per Infusion Phase by Group

    Time frame: Day 14 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours

    Infusion 2 (Day 14) - Heart rate at all time points by group

    "Phase" in this analysis refers to the infusion stage as defined in the protocol.

  12. ECG Measures at All Time Points by Group

    Time frame: Day 0 - Baseline (pre-infusion), During Infusion (@30 min), Post-Infusion (@60min)

    Infusion 1 (Day 0) - ECG measures at all time points by group

  13. ECG Measures at All Time Points by Group

    Time frame: Day 14 - Baseline (pre-infusion), During Infusion (@30 min), Post-Infusion (@60min)

    Infusion 2 (Day 14) - ECG measures at all time points by group

  14. Incidence of Treatment-Emergent Adverse Events (TEAEs)

    Time frame: The period of observation for collection of treatment-emergent adverse events extends from Day 0 treatment through the final visit at Day 28.

    Incidence of Treatment-Emergent Adverse Events (TEAE) by Treatment Group. A treatment emergent adverse event (TEAE) is an AE that either began following initiation of study treatment or was present prior to the initiation of the treatment, but increased in frequency or severity following initiation treatment, regardless of causality.

  15. Number of Subject Withdrawals Due to Treatment-Emergent Adverse Events (TEAEs)

    Time frame: The period of observation extends from Day 0 treatment through the final visit at Day 28

    Incidence of Treatment-Emergent Adverse Events (TEAE) by Treatment Group. A treatment emergent adverse event (TEAE) is an AE that either began following initiation of study treatment or was present prior to the initiation of the treatment, but increased in frequency or severity following initiation treatment, regardless of causality.

  16. Systematic Assessment for Treatment Emergent Effects-Systematic Inquiry (SAFTEE-SI) - Percent of Participants Reporting Experiencing Symptoms at "Moderate" or "Severe" Level for the 10 Most Frequently Reported Symptoms Post Randomization

    Time frame: Baseline (Day - 1), Follow-Up = reported at any assessment thereafter, including 7 hours after Infusions #1 and #2, Baseline 2 (Day 13) and final follow-up, including early termination visits.

    The Systematic Assessment for Treatment Emergent Effects-Systematic Inquiry (SAFTEE-SI): This is a self-rated 77-item questionnaire organized into 13 body areas assessing possible adverse events during the course of the trial.

Sponsors and collaborators

Lead sponsor

Massachusetts General Hospital

Other

Collaborators

  • Stanley Medical Research Institute

Registry information

Official study title

A Randomized Double-Blind, Placebo-Controlled, Proof of Concept Study of Intravenous Sodium Nitroprusside in Adults With Symptomatic Schizophrenia

Important dates

Study start
2015
Primary completion
2017
Study completion
2017
First posted
Jun 17, 2014
Registry last updated
Oct 2, 2018

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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